Human Immunodeficiency Virus (HIV) infection continues to be a global epidemic, with over 40 million people infected worldwide. While our understanding of HIV biology has greatly increased in the decades since its description, no vaccine is currently available and treatment continues to be elusive to many of those infected, particularly in developing countries. While much research has delved into the effects of the adaptive immune system on HIV infection, very little is known about how HIV is affected by the innate immune system. In particular there is almost nothing known about how HIV interacts with the pathogen recognition pathways that serve as our first line of cellular defense against viruses and other pathogens. My preliminary studies have reveled antagonism of host defense pathways through a disruption of the host interferon regulatory factor 3 (IRF3) protein, one of the integral molecules for several innate immune defense pathways. Two objectives have been outlined;1) define the mechanism of IRF3 downregulation by HIV, and 2) define the viral determinants that mediate this downregulation. Understanding how HIV affects our innate defense programs will have implications for developing novel therapeutics as well as provide information for rational vaccine design. PUBLIC HEALTH RELEVANCE: With more than 40 million people infected, HIV infection continues to be a global epidemic in which millions are without satisfactory treatment. A better understanding of how HIV interacts with our cellular defenses is necessary to design the next generation of HIV drugs as well as continue the search for an effective HIV vaccine.